Publications

Javed S, Chang YT, Lee YJ, Chang HC, Haque M, Lin YC,  Huang WH
Smith-Magenis syndrome protein Rai1 regulates body weight homeostasis through hypothalamic Bdnf-producing neurons and neurotrophin downstream signalling
Elife, 2023, in press
  • Using cell type-specific Cre-LoxP and CRISPR-mediated Rai1 deletions, we uncovered that Rai1 functions in a subset of Bdnf-producing neurons by maintaining energy homeostasis in mice. Patch-clamp electrophysiology found that Rai1 deletion in these neurons decreased neuronal firing. Reverse phase protein array found disrupted neurotrophin downstream signalling. Pharmacologically enhancing the Akt pathway confers a neuroprotective effect by delaying the obesity onset and glucose homeostasis in SMS mice
Chang HC, Lee YJ, Cho Y, Javed S, Haque M, Chang YT, Lin YC, Oram C, Huang WH
rAAV-CRISPRa therapy corrects Rai1 haploinsufficiency and rescues selective disease features in Smith-Magenis syndrome mice
J Biol Chem., 2023 Jan;299(1):102728
  • Using a CRISPR activation system, we developed the first gene therapy (more specifically, cis-regulatory therapy) that enhances the expression of the remaining healthy Rai1 allele in the hypothalamic PVH neurons of SMS mice. Transcriptomic analysis, neurobehavioral assays, and metabolic measurements indicate a partial rescue of Rai1-downstream molecules and SMS-like disease features in vivo
Chang YT, Kowalczyk M, Fogerson PM, Lee JY, Haque M, Adams EL, Wang DC, DeNardo LA, Tessier-Lavigne M, Huguenard JR, Luo L, Huang WH
Loss of Rai1 enhances hippocampal excitability and epileptogenesis in mouse models of Smith-Magenis syndrome
Proc Natl Acad Sci USA, 2022 Oct 25;119(43):e2210122119
  • We combined iDISCO+ whole brain imaging and activity mapping, in vivo EEG, ex vivo field recording, and patch-clamp electrophysiology experiments to understand how Rai1 loss in different population of neurons impact brain excitability. We discovered that Rai1 loss from the Emx1-lineage cortical excitatory neurons enhances intrinsic excitability and glutamatergic synaptic transmission of the hippocampal dentate gyrus granule cells. A calcium channel, Cav3.1, potentially participates in this process
Huang WH
Performing Single Cell Clonal Analysis in the Mouse Brain using Mosaic Analysis with Double Markers (MADM)
Methods Mol Biol., 2022 July;2515:59-74
  • In this methodology paper, I describe the practical considerations for employing a powerful genetic tool, MADM, to dissect neural development, morphogenesis, and demise at single-cell resolution. When coupled with genetic mutant alleles, MADM provides unprecedented resolution for understanding molecular and neuronal function in vivo
Javed S, Lee YJ, Xu J, Huang WH
Temporal dissection of Rai1 function reveals brain-derived neurotrophic factor as a potential therapeutic target for Smith-Magenis Syndrome
Hum Mol Genet., 2021 Dec 27;31(2):275-288
  • To understand the function of Rai1 in the adult mouse brain, we performed temporally-precise Rai1 deletion and uncovered an unexpected role for postnatal Rai1 in regulating energy homeostasis. RNA-seq found that Rai1 is continuously required to promote the expression of the Bdnf gene. Using neurobehavioral and metabolic assays, we demonstrate that globally enhancing Bdnf expression in SMS mice improves body weight, adiposity, neural function, and glucose homeostasis
​Javed S, Selliah T, Lee YJ, Huang WH
Dosage-Sensitive Genes in Autism Spectrum Disorders: From Neurobiology to Therapy 
Neurosci & Biobehav Rev., 2020 Nov;118:538-567
  • ​In this review, we synthesize current knowledge on the neurobiology of autism spectrum disorders with a defined genetic cause, such as SMS, Rett syndrome, and Angelman syndrome. We also discuss contemporary therapeutic efforts and point to promising future avenues
Luo L, Ambrozkiewicz MC, Benseler F, Chen C, Dumontier E, Falkner S, Furlanis E, Gomez AM, Hoshina N, Huang WH, Hutchison MA, Itoh-Maruoka Y, Lavery LA, Li W, Maruo T, Motohashi J, Pai ELL, Pelkey KA, Pereira A, Philips T, Sinclair JL, Stogsdill JA, Traunmuller L, Wang J, Wortel J, You W, Abumaria N, Beier KT, Brose N, Burgess HA, Cepko CL, Cloutier JF, Eroglu C, Goebbels S, Kaeser PS, Kay JN, Lu W, Luo L, Mandai K, McBain CJ, Nave KA, Prado MAM, Prado VF, Rothstein J, Rubesntein JL, Saher G, Sakimura K, Sanes JR, Scheiffele P, Takai Y, Umemori H, Verhage M, Yuzaki M, Zoghbi HY, Kawabe H, Craig AM
Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors 
Neuron, 2020 Apr 8;106(1):37-65.e5
  • This is a collaborative effort to report germline recombination in many commonly used nervous system Cre lines, providing an important guideline for the best practice for future Cre-LoxP experiments in mice
Huang WH, Wang DC, Allen, WE, Klope M, Hu H, Shamloo M, Luo L
Early Adolescent Rai1 Reactivation Reverses Transcriptional and Social Interaction Deficits In a Mouse Model of Smith-Magenis Syndrome 
Proc Natl Acad Sci USA, 2018, Oct 16;115(42):10744-10749
  • ​By generating a rescuable Rai1 allele, we demonstrated that Rai1 loss does not permanently damage neural function using neurobehavioral assays, Cre-LoxP recombination, and in vivo optogenetic assays. This provides hope that increasing Rai1 in the postnatal brain could be therapeutically beneficial for SMS mice and potentially, patients
​Yeh SY, Huang WH, Wang W, Ward CS, Chao ES, Wu Z, Tang B, Tang J, Sun JJ, van der Heijden ME, Gray PA, Xue M, Ray RS, Ren D, and Zoghbi HY
Respiratory network stability and modulatory response to substance P require Nalcn 
Neuron, 2017 Apr 19;94(2):294-303.e4
  • We performed fluorescence-activated cell sorting and discovered that Nalcn as an ion channel expressed in the RTN and preBötC neurons. Patch-clamp recordings found that Nalcn loss in mice disrupts rhythmic activity and modulatory response to substance P.  Telemetry and plethysmography found that Nalcn-deficient mice have increased apnea in awake and sleep states
​Huang WH, Guenthner CJ, Xu J, Nguyen N, Wilkinson AW, Gozani O, Chang HY, Shamloo M, Luo L
Molecular and Neural Functions of Rai1, The Causal Gene for Smith-Magenis Syndrome 
Neuron, 2016 Oct 19;92(2):392-406
  • We generated Rai1-flox mice and performed multi-omic analyses (ChIP-seq & RNA-seq), metabolic profiling, and neurobehavioral screens in mice. We found that Rai1 occupies the promoter/enhancer regions to regulate the expression of genes important for neural circuit assembly. Rai1-loss from Vglut2+ neurons recapitulates the most severe SMS-like features
Tupal S, Huang WH, Picardo MC, Ling GY, Del Negro CA, Zoghbi HY, Gray PA
Atoh1-dependent rhombic lip neurons are required for temporal delay between independent respiratory oscillators in embryonic mice 
Elife, 2014 May 14;3:e02265
  • We performed en bloc electrophysiological recordings in genetically-defined neurons in control and Atoh1 mutant mice and discovered that Atoh1 neurons help control the sequence of respiratory muscle activity during breathing by selectively inhibiting different populations of Dbx1 neurons
​​Huang WH, Tupal S, Huang TW, Ward CS, Neul JL, Klisch TJ, Gray PA, Zoghbi HY
Atoh1 governs the migration of postmitotic neurons that shape respiratory effectiveness at birth and chemoresponsiveness in adulthood 
​Neuron, 2012 Sep 6;75(5):799-809​
  • We pinpointed how a transcription factor Atoh1 regulates the development a group of brainstem neurons critical for regulating respiratory rhythm and chemosensitivity using Cre-LoxP genetic deletion, en bloc electrophysiological recordings, and in vivo plethysmography